Piperazine derivatives and pharmaceuticals containing the same

ABSTRACT

A piperazine derivative represented by the following formula: ##STR1## or a pharmaceutically acceptable salt thereof. The compound according to the present invention has strong anti-histaminic and anti-allergic affects and a high degree of safety, and is useful as an anti-histaminic agent, an anti-allergic agent and/or an anti-asthmatic drug. Also disclosed are pharmaceutical compositions containing the compound of formula 1 and a method for the treatment of allergic diseases comprising administering the claimed compound.

This application is a 371 of PCT/JP92/00833 filed Jul. 2,1992.

1. Technical Field

The present invention relates to novel piperazine derivatives andpharmaceuticals containing the same.

2. Background Art

Numerous piperazine derivatives have heretofore been synthesized andstudied for various pharmacological effects. Among them, those havingboth antiallergic and antihistamic effects are known.

For example, compounds having the diphenylmethylpiperazine skeleton aredisclosed in Japanese Patent Laid-Open Nos. 32474/1981, 149282/1982,11072/1991 and the like. These compounds, however, are accompanied byone or more drawbacks such that their pharmacological effects are stillinsufficient and/or they are questionable in safety.

With a view toward preparing a compound having still better antiallergicand antihistamic effects and in addition, having a high degree ofsafety, the present inventors have carried out an extensiveinvestigation. As a result, they have completed the present invention.

DISCLOSURE OF THE INVENTION

The present invention relates to a piperazine derivative represented bythe following formula (I): ##STR2## wherein B represents a phenyl orpyridinyl group, m stands for an integer of 2 or 3, p stands for aninteger of 1 or 2, R¹ represents a hydrogen or halogen atom, Arepresents --COOR², --Y--(CH₂)_(n) , --R³, ##STR3## in which R²represents a hydrogen atom or a lower alkyl group, Y represents a sulfuror oxygen atom, NH or ←CONH-- (← indicates a bond with a (CH₂)_(m)group), n stands for an integer of 0 to 3, R³ represents a cyano, amino,hydroxymethyl, 1H-tetrazole, 1-imidazolylcarbonyl, --CO--COOR⁴, --(CH₂)₁--COOR⁴ or --(CH₂)₁ --CONH--R⁵ group (R⁴ : hydrogen atom or lower alkylgroup, l: integer of 0 to 3; and R⁵ : 1H-tetrazole, thiazol-2-yl,thiazolin-2-yl, triazol-5-yl, trimethoxyphenyl or3,5-dimethyl-4-hydroxyphenyl group), X represents CH or a nitrogen atomand R⁶ represents a hydrogen atom or a lower alkoxyl group, ##STR4##with the proviso that either case where R¹, B, p, m and A represent ahydrogen atom, a phenyl group, 1, 2 and --NH--C₆ H₄ --COOR⁴,respectively, or where R¹, B, p, m and A represent a chlorine atom, aphenyl group, 1, 2 and --O--CH₂ COOH, respectively is excluded; or asalt thereof.

In addition, the present invention also relates to an antihistamic agentand an antiallergic agent each containing the piperazine derivative (I)as an active ingredient.

In the formula (I), examples of the lower alkyl group represented by R²or R⁴ include C₁₋₄ linear or branched alkyl groups, those of the loweralkoxyl group represented by R⁶ include C₁₋₄ linear or branched alkylgroups, and those of the halogen atom represented by R¹ includechlorine, bromine, fluorine and iodine atoms.

The piperazine derivative (I) according to the present invention can beconverted to a pharmaco-logically-acceptable salt thereof, for example,an acid-addition salt such as the hydrochloride, nitrate, sulfate,maleate, fumarate, oxalate, citrate, hydrobromate, succinate,sulfaminate, mandelate, malonate and phosphate or a base salt such asthe sodium salt, potassium salt, lithium salt or calcium salt.

The compounds (I) according to the present invention may havestereoisomers such as optical isomers because they may contain anasymmetric carbon atom. It is to be noted that these isomers are allembraced by the present invention.

The compounds (I) according to the present invention have excellentantihistamic and antiallergic effects and also a high degree of safetyas will be described later, so that they are effective as therapeuticagents for various allergic diseases, for example, as anti-inflammatoryagents, therapeutics for nephritis, hepatitis or pancreatitis,preventives and/or therapeutics for respiratory diseases, andanti-asthmatic drugs.

BEST MODES FOR CARRYING OUT THE INVENTION

The compound (I) of this invention can be prepared, for example, inaccordance with the following process:

Process A: ##STR5## wherein R¹, B, p, m and A have the same meanings asdefined above and Z is a halogen atom.

In other words, the compound (I) according to the present invention canbe prepared by reacting a piperazine derivative represented by theformula (II) with a compound represented by the formula (III) in thepresence of a base.

It is preferred to conduct the above reaction in a solvent which doesnot affect the reaction. Examples of the solvent include water; esterssuch as methyl acetate and ethyl acetate; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetoneand methyl ethyl ketone; halogenated hydrocarbons such asdichloromethane and chloroform; aromatic hydrocarbons such as benzene,toluene and xylene; acetonitrile; dimethylsulfoxide; anddimethylformamide. They may be used either singly or in combination. Thereaction temperature may be varied depending on the starting compoundsemployed. In general, it is advantageous to select a temperature withina range of from 0° C. to a reflux temperature under normal pressure.

Examples of the base include carbonates such as potassium carbonate,sodium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; alkali metal hydroxides such as potassium hydroxide,sodium hydroxide and lithium hydroxide; and organic bases such astriethylamine, diisopropylamine, DBU(1,8-diazabicyclo[5.4.0]-7-undecene).

When the compound represented by the formula (III) is a carboxylic acidester, the corresponding carboxylic acid can be obtained by subjectingthe invention compound (I), which has been prepared by the abovereaction, to hydrolysis in a manner known per se in the art. Theresulting carboxylic acid is then condensed with carbodiimidazole,5-amino-1H-tetrazole, 2-aminothiazole, 2-aminothiazolidine,5-aminotriazole, 3,4,5-trimethoxyaniline or3,5-dimethyl-4-hydroxyaniline, leading to the preparation of anotherinvention compound.

It is desirable to conduct the above condensation, in a manner known todate, in a solvent which does not affect the reaction. Examples of thesolvent include esters such as methyl acetate and ethyl acetate; amidessuch as dimethylformamide and diethylformamide; ethers such as diethylether, diisopropyl ether, tetrahydrofuran and dioxane; halogenatedhydrocarbons such as dichloromethane and chloroform; aromatichydrocarbons such as benzene, toluene and xylene; acetonitrile; anddimethylsulfoxide. These solvents can be used either singly or incombination. The reaction temperature may be varied depending on thestarting compounds employed. In general, it is advantageous to select atemperature within a range of from 0° C. to a reflux temperature undernormal pressure.

When the compound represented by the formula (III) is a cyano-containingcompound, the invention compound (I) prepared by the above reaction canbe converted to another invention compound containing a 1H-tetrazolegroup by reacting the invention compound (I) with tri-n-butyltin azidein the presence of a base. It is desirable to conduct the reaction in asolvent which does not affect the reaction. Examples of the solventinclude esters such as methyl acetate and ethyl acetate; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;halogenated hydrocarbons such as dichloromethane and chloroform;aromatic hydrocarbons such as benzene, toluene and xylene; anddimethylformamide. These solvents can be used either singly or incombination. The reaction temperature may be varied depending on thestarting compounds employed. In general, it is advantageous to select atemperature within a range of from room temperature to a refluxtemperature under normal pressure. As the base, those similar to thebases exemplified above can be employed.

Process B:

The invention compound can also be prepared by the following process:##STR6## wherein Z, R¹, B, p, m and A have the same meanings as definedabove.

In other words, the compound (I) according to the present invention canbe prepared by subjecting a compound represented by the formula (IV) anda compound represented by the formula (V) to condensation in thepresence of a base.

It is preferred to conduct the above reaction in a solvent which doesnot affect the reaction. Examples of the solvent include esters such asmethyl acetate and ethyl acetate; ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetoneand methyl ethyl ketone; halogenated hydrocarbons such asdichloromethane and chloroform; aromatic hydrocarbons such as benzene,toluene and xylene; acetonitrile; dimethylsulfoxide; anddimethylformamide. They can be used either singly or in combination. Thereaction temperature may be varied depending on the starting compoundsemployed. In general, it is advantageous to select a temperature withina range of from 0° C. to a reflux temperature under normal pressure. Asthe base, bases similar to those exemplified in the Process A areusable.

When the compound represented by the formula (V) is a carboxylic acidester or a cyano-containing compound, the invention compound so obtainedcan be converted to a corresponding invention compound of another typeby treating it in a similar manner to Process A.

When the starting compound (II) or (IV) has an asymmetric carbon atom inProcess A or Process B, the invention compound (I) so obtained includescorresponding stereoisomers.

Among the invention compounds (I) obtained as de-scribed above, thefollowings are representatives ones except for the compounds to bedescribed in Examples.

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]-N-3,4,5-trimethoxyphenylbenzamide

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]-N-(3,5-dimethyl-4-hydroxyphenyl)-benzamide

3-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]benzoicacid

3-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamide

2-[[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propyl]thio]benzoicacid

2-[[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propyl]thio]-N-1H-tetrazol-5-yl-benzamide

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]nicotinicacid

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-nicotinamide

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]benzoicacid

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]-N-1H-tetrazol-5-yl-benzamide

Ethyl 4-[[2-[4-[(4-chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]thio]benzoate

4-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]thio]-N-1H-tetrazol-5-yl-benzamide

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]phenylaceticacid

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-phenylacetamide

4-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-anthranylamide

Propyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]nicotinate

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-nicotinamide

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]thio]aceticacid

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]-3-indolecarboxylicacid

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethyl]-N-1H-tetrazol-5-yl-3-indoleamide

Butyl4-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-homopiperazinyl]propoxy]benzoate

4-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamide

Methyl2-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-homopiperazinyl]propoxy]naphthoate

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]propoxy]naphthoicacid

4-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-naphthamide

2-[2-[4-(Diphenylmethyl)-l-piperazinyl]ethoxy]-N-1H-triazol-5-yl-benzamide

2-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethyl]thio]-N-1H-tetrazol-5-yl-benzamide

2-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-nicotinamide

1-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethyl]-N-1H-tetrazol-5-yl-2-indoleamide

4-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-[N-1H-tetrazol-5-yl]-benzene

4-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-benzamide

4-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-3,4,5-trimethoxyphenyl-benzamide

4-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-thiazol-2-yl-benzamide

4-[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]-thio]benzoic acid

4-[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]-thio]-N-1H-tetrazol-5-yl-benzamide

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-anthranilic acid

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-anthranilamide

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-nicotinic acid

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-nicotinamide

1-[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]-2-indolecarboxylic acid

1-[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl]-2-N-1H-tetrazol-5-yl-indoleamide

4-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-benzonitrile

Butyl 2-[[3-[4-(diphenylmethyl)-1-piperazinyl]-propyl]thio]acetate

-2-[[3-[4-(Diphenylmethyl)-1-piperazinyl]propyl] -thio]acetic acid

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-acetamide

1-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-naphthoic acid

1-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-naphthoamide

Ethyl 2-[3-[4-(diphenylmethyl)-1-homopiperazinyl]-propoxy]benzoate

2-[3-[4-(Diphenylmethyl)-1-homopiperazinyl]-propoxy]-N-1H-tetrazol-5-yl-benzamide

Methyl 2-[3-[4-(diphenylmethyl)-1-homopiperazinyl]-propoxy]naphthoate

2-[3-[4-(Diphenylmethyl)-1-homopiperazinyl]-propoxy]naphthoic acid

2-[3-[4-(Diphenylmethyl)-1-homopiperazinyl]-propoxy]-N-1H-tetrazol-5-yl-naphthoamide

Propyl3-[2-[4-[2-(4-chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]benzoate

3-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

2-[[2-[4-[2-(4 -Chlorophenyl ) pyridylmethyl]-1-piperazinyl]ethyl]thio]benzoic acid

2-[[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethyl]thio]-N-1H-tetrazol-5-yl-benzamide

°2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]anthranilicacid

2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-anthranilamide

1-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1piperazinyl]ethyl]-3-ethoxycarbonyl-indole

1-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethyl]-N-1H-tetrazol-5-yl-3-indoleamide

3-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]benzonitrile

4-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]benzoylimidazole

2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-acetamide

2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]-1H-tetrazole-5-ylmethyl

4-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]propoxy]benzoicacid

4-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]propyl]-N-1H-tetrazol-5-yl-benzamide

Butyl3-[2-[4-[2-(4-chlorophenyl)pyridylmethyl]-1-homopiperazinyl]ethoxy]benzoate

3-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

Ethyl1-[2-[4-[2-(4-chlorophenyl)pyridylmethyl]-1-homopiperazinyl]ethoxy]naphthoate

1-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]ethoxy]naphthoicacid

1-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-naphthoamide

2-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]propoxy]benzoicacid

2-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamide

2-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]propoxy]naphthoicacid

2-[3-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-naphthoamide

2-[[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-ethyl]thio]benzoic acid

2-[[2-[4-(2-Phenyl-pyridylmethyl]-1-piperazinyl]-ethyl]thio]-N-1H-tetrazol-5-yl-benzamide

2-[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-ethoxy]anthranilic acid

2-[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-ethoxy]-N-1H-tetrazol-5-yl-anthranilamide

2-[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-ethoxy]nicotinic acid

2-[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-ethyl]-N-1H-tetrazol-5-yl-nicotinamide

Methyl 2-[3-[4-(2-phenyl-pyridylmethyl)-1-piperazinyl]propoxy]benzoate

2-[3-[4-(2-phenyl-pyridylmethyl)-1-piperazinyl]-propoxy]-N-1H-tetrazol-5-yl-benzamide

Propyl 2-[3-[4-(2-phenyl-pyridylmethyl)-1-piperazinyl]propoxy]naphthoate

2-[3-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-propoxy]naphthoic acid

2-[3-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]-propoxy]-N-1H-tetrazol-5-yl-naphthoamide

3-[2-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]ethoxy]benzoic acid

3-[2-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

Methyl1-[2-[4-(2-phenyl-pyridylmethyl)-1-homopiperazinyl]ethoxy]naphthoate

1-[2-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]ethoxy]naphthoic acid

1-[2-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-naphthoamide

Ethyl2-[3-[4-(2-phenyl-pyridylmethyl)-1-homopiperazinyl]propoxy]benzoate

2-[3-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamide

Ethyl2-[3-[4-(2-phenyl-pyridylmethyl)-1-homopiperazinyl]propoxy]naphthoate

2-[3-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]propoxy]naphthoicacid

2-[3-[4-(2-Phenyl-pyridylmethyl)-1-homopiperazinyl]propoxy]-N-1H-tetrazol-5-yl-naphthoamide

The compound (I) according to the present invention can be formulatedinto dosage forms suited for oral administration or parenteraladministration by adding one or more pharmaceutically-acceptableauxiliary agents thereto.

Solid dosage forms for oral administration include tablets, powders,granules and capsules. The invention compound (I) can be formulated intosuch a solid preparation by combining it with one or more suitableadditives such as excipients, e.g., lactose, mannitol, corn starch orcrystalline cellulose; binders, e.g., a cellulose derivative, gum arabicor gelatin; disintegrators, e.g., calcium carboxymethylcellulose; andlubricants such as talc and magnesium stearate. The solid preparation soobtained can be converted into an enteric coated one by coating it witha coating base material such as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate, cellulose acetatephthalate or a methacrylate copolymer.

Exemplary liquid preparations for oral administration include emulsions,solutions, suspensions, syrups and elixirs. The compound (I) accordingto the present invention can be prepared in the form of a liquidpreparation by combining an inert diluent such as purified water orethanol. In addition to the inert diluent, auxiliary agents such as ahumectant and a suspending agent, a sweetener, a taste improver, anaromatic agent and/or an antiseptic can be added. The compound can alsobe used in the form of an aerosol preparation which is formulated in amanner known per se in the art.

Examples of the liquid preparation for parenteral administration includeinjections. The invention compound (I) can be formulated into the formof an injection by combining the compound with water, ethanol, glycerinand a conventional surfactant. Further, the compound can also be used inthe form of a surface application drug such as an inhalation, liquid forexternal use, ophthalmic solution, nasal drops or ointment.

The dosage of the compound (I) of the present invention varies dependingon the age, weight, conditions, therapeutic effects, administrationmethod, administration period, etc. In general, it is desirable toorally administer the compound (I) at a daily dosage of 1-500 mg/day,particularly 5-50 mg/day, in 1-3 portions a day or to parenterallyadminister it at a dosage of 0.1-500 mg/day in one to several portions aday.

EXAMPLE

The present invention will hereinafter be described more specifically bythe following examples. It is, however, to be borne in mind that thepresent invention is by no means limited to or by them. In each table,Ph and Py indicate a phenyl group and a 2-pyridinyl group, respectively.

EXAMPLE 1

Methyl3-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoate##STR7##

In acetone, 16.0 g (38 mmol) of2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethylchloride.dihydrochloride and 18.3 g of potassium carbonate weresuspended, followed by the addition of 6.9 g (45 mmol) of methyl3-hydroxybenzoate. The resulting suspension was refluxed at 70° C. for24 hours. After the reaction mixture was allowed to cool down, 200 ml ofwater were added, followed by extraction with 200 ml portions of ethylacetate twice. The ethyl acetate layers were washed with water and driedover anhydrous magnesium sulfate. The solvent was thereafter distilledoff. The residue so obtained was purified by chromatography on a silicagel column (ethyl acetate:n-hexane=1:1), whereby 12 g of the titlecompound were obtained.

Yield: 68%. Melting point (decomposition point): 200°-205° C.(dihydrochloride) MS (m/z): 464(M⁺) IR (nujol) cm⁻¹ : 3400, 2350, 1710NMR (DMSO-d₆) δ: (oxalate) 2.55(4H,brs), 3.23(4H,brs), 3.40(2H,t),3.85(3H,s), 4.35(2H,t), 4.47 (1H,s), 7.22-7.59(13H,m)

EXAMPLE 2

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoic acid##STR8##

In 200 ml of ethanol, 10 g of the methyl3-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]benzoateobtained in Example 1 and 50 ml of 10% sodium hydroxide were dissolved,followed by stirring at 50° C. for one hour. After the reaction mixturewas allowed to cool down, the solvent was distilled off under reducedpressure. Water (200 ml) was added to the residue, followed by theaddition of acetic acid to adjust its pH to 4.0. The resulting mixturewas extracted with 200 ml portions of ethyl acetate twice. The ethylacetate layers so obtained were washed with water and then dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure. The residue so obtained was purified by chromatography on asilica gel column (chloroform:methanol=10:1), whereby 6.6 g of the titlecompound were obtained.

Yield: 69%. Melting point (decomposition point): 202°-203° C. MS (m/z):450(M⁺) IR (nujol) cm⁻ : 3400, 1705, 1580 NMR (DMSO-d₆ ) δ:2.77(1H,brs), 3.35-3.42(8H,m), 3.50(2H,t), 4.46(2H,t), 4.51(1H,s),7.22-7.58(13H,m)

EXAMPLES 3-39

The compounds of Examples 3-39 shown in Tables 1-8 were each obtained inaccordance with the procedures of Example 1 or Example 2. The names ofthe respective compounds will be described below.

EXAMPLE 3

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoate

EXAMPLES 4 & 5

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoic acid

EXAMPLE 6

Methyl4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoate

EXAMPLE 7

4-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoic acid

EXAMPLE 8

Methyl 2-[2-[4-(diphenylmethyl)-1-piperazinyl]-ethoxy]benzoate

EXAMPLE 9

2-[2-[4-(Diphenylmethyl]-1-piperazinyl]ethoxy]-benzoic acid

EXAMPLE 10

Methyl2-[3-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]benzoate

EXAMPLE 11

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]benzoicacid

EXAMPLE 12

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzylalcohol

EXAMPLE 13

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzonitrile

EXAMPLE 14

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzonitrile

EXAMPLE 15

[3-[4-(Diphenylmethyl]-1-piperazinyl]N-propionyl]anthranilic acid

EXAMPLE 16

Methyl1-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]naphthoate

EXAMPLE 17

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]naphthoicacid

EXAMPLE 18

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]naphthoate

EXAMPLE 19

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]naphthoicacid

EXAMPLE 20

3-[1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxycarbonylmethyl]-2-methyl-5-methoxy-indole

EXAMPLE 21

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-2-methyloxycarbonyl-indole

EXAMPLE 22

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-3-indolecarboxylicacid

EXAMPLE 23

Methyl1-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-2-methyl-5-methoxy-3-indole-acetate

EXAMPLE 24

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-2-methyl-5-methoxy-3-indoleaceticacid

EXAMPLE 25

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-2-indolecarboxylicacid

EXAMPLE 26

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]phenylaceticacid

EXAMPLE 27

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]phenylacetate

EXAMPLE 28

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]nicotinate

EXAMPLE 29

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]nicotinicacid

EXAMPLE 30

8-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-quinolin-N-(1H)-2-one

EXAMPLE 31

2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]benzoicacid

EXAMPLE 32

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]benzoate

EXAMPLE 33

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]benzoicacid

EXAMPLE 34

Methyl 2-[2-[4-(2-phenyl-pyridylmethyl)-1-piperazinyl]ethoxy]benzoate

EXAMPLE 35

2-[2-[4-(2-Phenyl-pyridylmethyl)-1-piperazinyl]ethoxy]benzoic acid

EXAMPLE 36

Ethyl 4-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]butyrate

EXAMPLE 37

4-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]butyric acid

EXAMPLE 38

Methyl 2-[2-[4-(diphenyl)-1-homopiperazinyl]ethoxy]benzoate

EXAMPLE 39

2-[2-[4-(Diphenyl)-1-homopiperazinyl]ethoxy]benzoic acid

                                      TABLE 1                                     __________________________________________________________________________    EX.                                                                              R.sup.1                                                                         B m p A           Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                  __________________________________________________________________________    3  Cl                                                                              Ph                                                                              2 1                                                                                ##STR9##   Decomposition point 210-214 (Dihydrochloride)                                          464  IR(nujol):1720 NMR(CDCl.sub.3):(2HCl)                                         3.56(4H, brs), 3.83(3H, s), 4.04(2H,                                          t), 4.40(4H, brs), 4.63(2H, t),                                               5.00(1H, s), 6.95-7.88(13H, m)           4  Cl                                                                              Ph                                                                              2 1                                                                                ##STR10##  Decomposition point 216-218 (Dihydrochloride)                                          450  IR(nujol):1690 NMR(CDCl.sub.3):2.34(4                                         H, brs), 2.70(2H, t), 2.97(4H, brs),                                          .94(1H, s), 4.03(2H,                                                          brs), 6.78-7.81(13H, m)                  5  Cl                                                                              Ph                                                                              2 1                                                                                ##STR11##  193-195 (1/2 Fumarate)                                                                 450  IR(nujol):1690 NMR(DMSO-d.sub.6):2.36                                         (4H, brs), 2.70(4H, brs), 2.82(2H,                                            t), 4.25 (2H, t), 4.33(1H, s),                                                6.62(1H, s), 6.98-7.61(13H, m),                                               8.25(2H, brs)                            6  Cl                                                                              Ph                                                                              2 1                                                                                ##STR12##  Decomposition point 197-199 (Dihydrochloride)                                          464  IR(nujol):3400, 1720 NMR(DMSO-d.sub.6                                         ):(oxalate) 2.54(4H, brs), 3.22(4H,                                           brs), 3.40(2H, t), 4.37(2H, t), 4.47                                          1H, s), 7.05-7.93(13H, m)                7  Cl                                                                              Ph                                                                              2 1                                                                                ##STR13##  Decomposition point 230-232 (Dihydrochloride)                                          450  IR(nujol):3400, 1700 NMR(DMSO-d.sub.6                                         ):2.77(1H, brs), 3.34(8H, brs),                                               3.50(2H, brs), 4.51(3H, brs),                                                 7.05-7.92(13H, m)                        __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    EX.                                                                              R.sup.1                                                                         B m p A           Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                  __________________________________________________________________________    8  H Ph                                                                              2 1                                                                                ##STR14##  Decomposition point 211-213 (Dihydrochloride)                                          430  IR(nujol):3380, 1720 NMR(CDCl.sub.3):                                         (2HCl)3.58(4H, brs), 3.83(3H, s),                                             4.01(4H, brs), 4.48(2H, t), 4.61(2H,                                          t), 5.02(1H, s), 6.95-7.91(14H, m)       9  H Ph                                                                              2 1                                                                                ##STR15##  178-179 (Maleate)                                                                      416  IR(nujol):1675 NMR(DMSO-d.sub.6):2.51                                         (4H, brs), 3.38(4H, brs), 3.46(2H,                                            t), 4.37(2H, t), 4.46(1H, s),                                                 7.04-7.70(14H, m)                        10 Cl                                                                              Ph                                                                              3 1                                                                                ##STR16##  114-117 (Maleate)                                                                      478  NMR(DMSO-d.sub.6):2.15(2H, m),                                                2.30(2H, m), 2.83(2H, brs), 3.15                                              (2H, brs), 3.31(2H, t), 3.50(2H, m),                                          .78(3H, s), 4.13(2H, t), 4.56(1H,                                             s), 6.14(4H, s), 7.05-7.73(13H, m)       11 Cl                                                                              Ph                                                                              3 1                                                                                ##STR17##  -- powder                                                                              464  IR(nujol):3420, 1680 NMR(DMSO-d.sub.6                                         ):(2HCl)2.21(2H, t), 3.15(4H, brs),                                           3.35(4H, brs), 3.57(1H, s), 3.60(2H,                                          m), 4.14 (2H, t), 7.03-7.72(14H, m)      12 Cl                                                                              Ph                                                                              2 1                                                                                ##STR18##  powder   436  IR(nujol):3350 NMR(CDCl.sub.3):2.42(4                                         H, brs), 2.54 (4H, brs), 2.63(1H,                                             s), 2.73(2H, brs), 4.20(2H, brs),                                             4.22(1H, s) 4.60(2H, s),                                                      6.88-7.35(13H, m)                        __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    EX.                                                                              R.sup.1                                                                         B m p A            Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                 __________________________________________________________________________    13 Cl                                                                              Ph                                                                              2 1                                                                                ##STR19##   Decomposition point 160 (Oxalate)                                                      431  IR(nujol):2220 NMR(DMSO-d.sub.6):(Ox                                          alate)2.52 (4H, m), 3.25(4H, m),                                              3.41(2H, t), 4.46(2H, t), 4.49(1H,                                            s), 7.13-7.75(13H, m)                   14 Cl                                                                              Ph                                                                              2 1                                                                                ##STR20##   168-170  431  IR(nujol):2220, 1680 NMR(DMSO-d.sub.                                          6):(fumarate)2.51 (4H, brs),                                                  3.30(4H, brs), 3.54 (2H, t),                                                  4.39(2H, t), 4.55(1H, s), 6.15(4H,                                            s), 7.24-7.53(13H, m)                   15 H Ph                                                                              2 1                                                                                ##STR21##   Decomposition point 223                                                                443  IR(nujol):3580, 3450,                                                         1670 NMR(DMSO-d.sub.6):2.70-3.10(6H,                                           m), 2.40-2.50(12H, m), 3.14(2H, t)                                           .36(1H, s), 7.01-7.43(12H, m),                                                7.95-7.98(1H, m), 8.45-8.48(1H, m)      16 Cl                                                                              Ph                                                                              2 1                                                                                ##STR22##   Decomposition point 177-180 (Dihydrochloride)                                          514  IR(nujol):3400, 1720,                                                         1600 NMR(CDCl.sub.3):3.54(4H, brs),                                           3.83 (4H, brs), 4.03(3H, s), 4.43                                             (2H, brs), 4.72(2H, brs), 4.95 (1H,                                           s), 7.28-7.93(15H, m)                   17 Cl                                                                              Ph                                                                              2 1                                                                                ##STR23##   130-131  500  IR(nujol):3200, 1580,                                                         1410 NMR(CDCl.sub.3):2.42(4H, brs),                                           .53(4H, brs), 2.68(2H, t), 4.22(1H,                                           s), 4.51(2H, t), 7.10-8.35(15H,         __________________________________________________________________________                                          m)                                  

                                      TABLE 4                                     __________________________________________________________________________    EX.                                                                              R.sup.1                                                                          B m  p A                 Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1),                   __________________________________________________________________________                                                 NMR(ppm)                         18 Cl Ph                                                                              2  1                                                                                ##STR24##        Decomposition point 197-200 (Dihydrochlorid                                   e)       514  IR(nujol):3500, 1710, 1600                                                    NMR(CDCl.sub.3):3.75(2H, t),                                                  3.96 (3H, s), 4.12(4H, brd),                                                  4.53 (4H, brd), 4.63(2H, t),                                                  5.05 (1H, s), 7.36-8.33(15H,                                                  m)                               19 Cl Ph                                                                              2  1                                                                                ##STR25##        192-194 (Dihydrochloride)                                                              500  IR(nujol):3450, 1690, 1600                                                    NMR(DMSO-d.sub.6):(2HCl)3.03                                                  2H, brs), 3.76(5H, brs),                                                      4.45(6H, brt), 7.40-8.34(16H,                                                  m)                              20 Cl Ph                                                                              2  1                                                                                ##STR26##         -- (amorphous)                                                                        531  NMR(DMSO-d.sub.6):2.18(4H,                                                    brs), 2.29 (3H, s), 2.35(4H,                                                  brs), 2.51 (2H, t), 3.59(2H,                                                  s), 3.70(3H, s), 4.07(2H,                                                     t), 4.21(1H, s), 6.57-                                                        7.42(12H, m), 10.65(1H,                                                       brs)                             21 Cl Ph                                                                              2  1                                                                                ##STR27##        -- (foam)                                                                              487  NMR(DMSO-d.sub.6):2.25(4H,                                                    brs), 2.46(4H, brs),                                                          2.67(2H, t), 3.81 (3H, s),                                                    4.24(1H, s), 4.30(2H, t),                                                     7.15-7.57(11H, m),                                                            7.54-7.57(1H, m),                                                             8.03-8.06(1H, m), 8.12(1H,                                                    s)                               22 Cl Ph                                                                              2  1                                                                                ##STR28##        Decomposition point 105-110                                                            474  IR(nujol):3350, 1680                                                          NMR(DMSO-d.sub.6):2.28(4H,                                                    brs), 2.70(2H, t), 3.35(4H,                                                   brs), 4.28(1H, s), 4.32(2H,                                                   t), 7.16-7.99(14H, m),                                                        8.03(1H, s)                      __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A                  Melting point(°C.)                                                              MS(M.sup.+)                                                                         IR(cm.sup.-1),                   __________________________________________________________________________                                                 NMR(ppm)                         23 Cl                                                                              Ph                                                                              2 1                                                                                ##STR29##         -- (amorphous)                                                                         545   IR(nujol):                                                                    1730 NMR(DMSO-d.sub.6):                                                       2.25(4H, brs), 2.31 (3H, s),                                                  2.44(4H, brs), 2.50(2H, t),                                                   3.54(3H, t), 3.73(3H, s),                                                     4.12(2H, t), 4.27(1H, s),                                                     6.66-7.44(12H, m)                24 Cl                                                                              Ph                                                                              2 1                                                                                ##STR30##         Decomposition point 198                                                                487 (Decarbo- xylated)                                                              IR(nujol): 3350, 1700                                                         NMR(DMSO-d.sub.6): 2.36(3H,                                                   s), 2.50 (4H, brs), 2.80(2H,                                                  brs), 3.30 (4H, brs),                                                         3.60(2H, s), 3.74(3H, s),                                                     4.54(3H, brs),                                                                6.72-7.45(12H, m),                                                            11.36(1H, brs)                   25 Cl                                                                              Ph                                                                              2 1                                                                                ##STR31##         Decomposition point 171-177                                                            429 (Decarbo- xylated)                                                              IR(nujol): 3400, 1590                                                         NMR(DMSO-d.sub.6): 2.28(4H,                                                   brs), 2.63(2H, t), 3.60(5H,                                                   brs), 4.27(1H, s), 4.68(2H,                                                   t), 7.09(1H, s),                                                              7.00-7.62(13H, m)                26 Cl                                                                              Ph                                                                              2 1                                                                                ##STR32##         Decomposition point 184                                                                464   IR(nujol): 3400, 1720, 1600                                                   NMR(CDCl.sub.3): 2.51(4H,                                                     brs), 2.76 (4H, brs),                                                         2.92(2H, t), 3.56(2H, s),                                                     4.11(2H, t), 4.22(1H, s),                                                     5.45 (1H, brs),                                                               6.77-7.36(13H, m)                27 Cl                                                                              Ph                                                                              2 1                                                                                ##STR33##         Decomposition point 168                                                                478   IR(nujol): 3400, 1720, 1590                                                   NMR(DMSO-d.sub.6):                                                            (2HCl)2.60(4H, brs),                                                          2.98(4H, brs), 3.35(2H, t),                                                   3.50 (3H, s), 3.66(2H, s),                                                    4.38(2H, t), 4.82(1H, s),                                                     6.94-7.53(13H,                   __________________________________________________________________________                                                 m)                           

                                      TABLE 6                                     __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A            Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                 __________________________________________________________________________    28 Cl                                                                              Ph                                                                              2 1                                                                                ##STR34##   182-184  465  IR(nujol): 3300, 1720, 1580                                                   NMR(DMSO-d.sub.6): (2HCl)2.87(4H,                                             brs), 3.23(4H, brs), 3.57(2H, t),                                             3.77(3H, s), 4.67(1H, s), 4.73(2H,                                            t), 7.16-8.41(12H, m)                   29 Cl                                                                              Ph                                                                              2 1                                                                                ##STR35##   173-174  451  IR(nujol): 3150, 1700, 1580                                                   NMR(DMSO-d.sub.6): (2HCl)2.85 (4H,                                            brs), 3.54(4H, brs), 3.66 (2H, t),                                            4.57(1H, s), 4.70(2H,                                                         t), 7.13-8.37(12H, m), 10.20(1H,                                              brs)                                    30 Cl                                                                              Ph                                                                              2 1                                                                                ##STR36##   Decomposition point 245-247                                                            473   IR(nujol): 3400, 1670, 1610                                                  NMR(DMSO-d.sub.6): (2HCl)3.22 (4H,                                            brs), 3.76(8H, brs), 4.49(1H, s),                                             6.52-7.92 (14H, m), 11.12(1H, s)        31 Cl                                                                              Py                                                                              2 1                                                                                ##STR37##   -- (amorphous)                                                                         451  IR(nujol): 3350, 1690 NMR(DMSO-d.sub                                          .6): 2.35(4H, brs), 2.62(4H, brs),                                            2.75(2H, t), 4.23(2H, t), 4.45(1H,                                            s), 6.97- 7.78(11H, m),                                                       8.44-8.46(1H, m)                        32 Cl                                                                              Ph                                                                              2 2                                                                                ##STR38##   Decomposition point 157 (Dihydrochloride)                                              478  IR(nujol): 3400, 1720 NMR(DMSO-d.sub                                          .6): (2HCl)2.09(4H, m), 3.19(6H,                                              m), 3.57(1H, s), 3.61(2H, t),                                                 3.69(3H, s), 4.47(2H, t),                                                     7.10-7.74(13H, m)                       __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A           Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                  __________________________________________________________________________    33 Cl                                                                              Ph                                                                              2 2                                                                                ##STR39##  Decomposition point 164 (Dihydrochloride)                                              464  IR(nujol): 3350, 1700 NMR(DMSO-d.sub.                                         6): (2HCl)2.09 (4H, m), 3.29(6H, m),                                          .57(1H, s), 3.60(2H, t), 4.47(2H,                                             t), 7.05-7.73(14H, m)                    34 H Py                                                                              2 1                                                                                ##STR40##  -- (oil) 431  IR(nujol): 1725                          35 H Py                                                                              2 1                                                                                ##STR41##  -- (powder)                                                                            417  IR(nujol): 3350, 1708 NMR(DMSO-d.sub.                                         6): 2.36(4H, brs), 2.63(4H, brs),                                             2.76(2H, t), 4.23 (2H, t), 4.40(1H,                                           s), 6.97-7.77 (12H, m),                                                       8.30-8.44(1H, m)                         36 Cl                                                                              Ph                                                                              3 1 COOCH.sub.2 CH.sub.3                                                                      --       400  IR(neat): 1730                                                  (Oil)         NMR(DMSO-d.sub.6): 1.16(3H, t),                                               1.61-                                                                         1.69(2H, m), 2.08-2.50(10H, m),                                               3.31(2H, brs), 4.01(2H, q),                                                   4.29(1H, s), 7.15-7.43(9H, m)            37 Cl                                                                              Ph                                                                              3 1 COOH        Decomposition                                                                          372  IR(neat): 3400, 1710                                            point 183-185 NMR(DMSO-d.sub.6): 1.57-1.68(2H,                                              m),                                                                           2.21(2H, t), 2.30-2.43(8H, m),                                                2.40(2H, brs), 4.30(1H, s)                                                    7.15-7.44(9H, m)                         __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A           Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                  __________________________________________________________________________    38 H Ph                                                                              2 2                                                                                ##STR42##  63-64    444  IR(nujol): 3100, 1705,                                                        1601 NMR(CDCl.sub.3): 1.74-1.80(2H,                                           m), 2.65(4H, dt), 2.82(2H, t),                                                2.92(2H, t), 3.30(2H, t), 3.82(3H,                                            s), 4.14(2H, t) 4.59(1H, s),                                                  6.94-7.79(14H, m)                        39 H Ph                                                                              2 2                                                                                ##STR43##  -- (foam) (Dihydrochloride)                                                            429  IR(neat): 3005, 1713,                                                         1558 NMR(CDCl.sub.3): 1.89-1.93(2H,                                           m), 2.65(2H, t), 2.76(2H, t),                                                 2.94(2H, t), 3.07(4H, dt), 4.37(2H,                                           t), 4.57(1H, s), 5.33(1H, brs),                                               6.99-7.92(14H, m)                        __________________________________________________________________________

EXAMPLE 40

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoylimidazol##STR44##

In dimethylformamide, 1.5 g (3.3 mmol) of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoicacid, which had been obtained in Example 4, were dissolved. Under icecooling, 1.35 g (8.3 mmol) of carbodiimidazole were added to theresulting solution, followed by stirring at 80° C. for 20 minutes. Afterthe reaction mixture was allowed to cool down, water was added and theresulting mixture was then extracted with ethyl ether. The ethyl etherlayer was dried over anhydrous magnesium sulfate. The solvent wasthereafter distilled off under reduced pressure. The residue so obtainedwas purified by chromatography on a column (chloroform), whereby thetitle compound was obtained. Melting point: powder (oxalate)

MS (m/z): 500(M⁺) IR (nujol) cm⁻¹ : 1705 NMR (DMSO-d₆) δ: (oxalate)2.38(2H,brs), 2.85(2H,brs), 3.12(2H,brs), 3.31(2H,brs), 3.40(2H,t),4.34(2H,m), 4.48(1H,s), 6.95-7.68(13H,m), 7.97 (1H,s), 8.80(1H,s)

EXAMPLE 41

2- [2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl ]ethoxy]-N-1H-tetrazol-5-yl-benzamide ##STR45##

In dimethylformamide, 1.5 g (3.3 mmol) of the2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]benzoicacid, which had been obtained in Example 4, were dissolved. Under icecooling, 1.35 g (8.3 mmol) of carbodiimidazole were added to theresulting solution, followed by stirring at 80° C. for 20 minutes. Thereaction mixture was allowed to cool down to room temperature. To thereaction mixture, 446 mg (4.3 mmol) of 5-amino-1H-tetrazole-H₂ O wereadded, followed by stirring at 100° C. for one hour. The reactionmixture was poured into ice water to precipitate crystals. The crystalsthus precipitated were collected by filtration and then purified bythin-layer chromatography, whereby 700 mg of the title compound wereobtained. Yield: 39%

(Sodium salt)

Melting point (decomposition point): 178° C.

    ______________________________________                                        Elemental analysis (1.2.H.sub.2 O)                                                      C          H      N                                                 ______________________________________                                        Calculated: 57.74        5.28   17.45                                         Found:      57.90        5.14   17.10                                         ______________________________________                                    

IR (nujol) cm⁻¹ : 3300, 1660 NMR (DMSO-d6) δ: 2.06(4H,brs),2.44(4H,brs), 2.74(2H,t), 4.05(1H,s), 4.29(2H,t), 7.05-7.93(14H,m)

(Hydrochloride)

Melting point (decomposition point): 197°-200° C. MS (m/z): 517(M⁺) IR(nujol) cm⁻¹ : 3400, 1680

EXAMPLE 42-59

In accordance with the procedures of Example 41, the compounds ofExamples 42-59 shown in Tables 9-12 were obtained. The names of thecompounds will be described below.

EXAMPLE 42

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

EXAMPLE 43

[3-[4-(Diphenylmethyl)-1-piperazinyl]N-propionyl]-N-1H-tetrazol-5-yl-anthranilamide

EXAMPLE 44

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]-N-1H-tetrazol-5-yl-benzamide

EXAMPLE 45

2-[3-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamide

EXAMPLE 46

2-[3-[4-(Diphenylmethyl)-1-piperazinyl]propoxy]-N-1H-tetrazol-5-yl-benzamid

EXAMPLE 47

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-naphthoamide

EXAMPLE 48

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-naphthoamide

EXAMPLE 49

2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-N-1H-tetrazol-5-yl-anthranilamide

EXAMPLE 50

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-acetamide

EXAMPLE 51

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-N-1H-tetrazol-5-yl-3-indoleamide

EXAMPLE 52

1-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]-N-1H-tetrazol-5-yl-2-indoleamide

EXAMPLE 53

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-phenylacetamide

EXAMPLE 54

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-nicotinamide

EXAMPLE 55

2-[2-[4-[(2-Phenyl-pyridylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzoicacid amide

EXAMPLE 56

2-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

EXAMPLE 57

2-[2-[4-[2-(4-Chlorophenyl)pyridylmethyl]-1-piperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzoicacid amide

EXAMPLE 58

2-[4-[(4-Chlorophenyl)phenylmethyl]-1-homopiperazinyl]ethoxy]-N-1H-tetrazol-5-yl-benzamide

EXAMPLE 59

2-[2-[4-(Diphenylmethyl)-1-homopiperazinyl]-ethoxy]-N-1H-tetrazol-5-yl-benzamide

                                      TABLE 9                                     __________________________________________________________________________    EX.                                                                              R.sup.1                                                                         B  m p A               Melting point(°C.)                                                              MS(M.sup.+)                                                                          IR(cm.sup.-1),                    __________________________________________________________________________                                                NMR(ppm)                          42 Cl                                                                              Ph 2 1                                                                                ##STR46##      Decomposition point 178                                                                518    IR(nujol):3175,                                                               1640 NMR(DMSO-d.sub.6):2.32(4H                                                , brs), 2.56 (2H, brs),                                                       2.75(2H, t), 3.45(2H, brs),                                                   4.14(2H, t), 4.31(1H, s),                                                     7.16-7.46(12H, m), 7.63(2H,                                                   brs)                              43 H Ph 2 1                                                                                ##STR47##      -- (powder)     NMR(DMSO-d.sub.6):2.22(2H,                                                    brs), 2.35  (2H, brs),                                                        2.76(2H, t), 3.18(2H, brs),                                                   4.23(2H, t), 4.33(1H, t),                                                     6.88(1H, s), 7.16-7.44(14H,                                                   m), 7.61(1H, s), 9.65(1H, s)      44 Cl                                                                              Ph 2 1                                                                                ##STR48##      190-193 (Dihydrochloride)                                                              533    IR(nujol):3200,                                                               1690 NMR(DMSO-d.sub.6):(2HCl)2                                                .89(4H, brs), 3.17(1H, s),                                                    3.26(2H, t), 3.38(2H, t),                                                     3.90(4H, brs), 4.84(1H, s),                                                   7.27-7.76(13H, m), 11.89(1H,                                                  s)                                45 Cl                                                                              Ph 3 1                                                                                ##STR49##      -- (Powder)     IR(nujol):3350,                                                               1650 NMR(DMSO-d.sub.6):1.96(2H                                                , brs), 2.29 (2H, brs),                                                       2.40-2.60(4H, m), 3.48 (6H,                                                   brs), 4.19(2H, t), 4.29(1H,                                                   s), 7.07-7.52(12H, m),                                                        7.80(1H, brs)                     46 H Ph 3 1                                                                                ##STR50##      194-199 (Dihydrochloride)                                                              497    IR(nujol):2450,                                                               1680 NMR(DMSO-d.sub.6);(2HCl)2                                                .20(2H, t), 3.32(3H, brs),                                                    3.63(8H, brd), 4.21(2H, t),                                                   7.08-7.75(15H, m), 11.88(1H,                                                  s)                                __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A                   Melting point(°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1),                   __________________________________________________________________________                                                 NMR(ppm)                         47 Cl                                                                              Ph                                                                              2 1                                                                                ##STR51##                   567  IR(nujol): 3400, 1670, 1600                                                   NMR(DMSO-d.sub.6): 2.25(4H,                                                   brs), 2.64(4H, brs),                                                          2.86(2H, t), 4.26(1H, s),                                                     4.36(12H, t), 7.18-8.09(17H,                                                  m)                               48 Cl                                                                              Ph                                                                              2 1                                                                                ##STR52##          Decomposition point 196-197 (Dihydrochlorid                                   e)       567  IR(nujol): 2400, 1680, 1580                                                   MR(DMSO-d.sub.6):                                                             (2HCl)2.83(4H, brs),                                                          3.61(2H, t), 3.80(4H, brs),                                                   4.43(2H, t), 4.65(1H, s),                                                     7.35- 8.19(16H, m),                                                           12.51(1H, brs)                   49 Cl                                                                              Ph                                                                              2 1                                                                                ##STR53##          Decomposition point 171                                                                516  NMR(DMSO-d.sub.6): 2.33(4H,                                                   brs), 2.89(4H, brs),                                                          3.27(2H, t), 3.88 (2H, t),                                                    4.27(1H, s), 6.59-6.78(2H,                                                    m), 6.96(1H, s),                                                              7.18-7.50(10H,                                                                m), 7.83-7.86(1H, m),                                                         10.79(1H, s)                     50 Cl                                                                              Ph                                                                              2 1                                                                                ##STR54##          Decomposition point 168 (Dihydrochloride)                                              455  IR(nujol): 3400, 3170, 1700                                                   NMR(DMSO-d.sub.6):                                                            (2HCl)2.09(2Hs), 3.10(4H,                                                     brs), 3.46(2H, t), 3.65 (4H,                                                  brs), 3.94(2H, brs),                                                          4.30(2H, s), 7.34-7, 48(5H,                                                   m), 7.76(7H, brs)                51 Cl                                                                              Ph                                                                              2 1                                                                                ##STR55##          Decomposition point 162                                                                540  IR(nujol): 3200, 1670                                                         NMR(DMSO-d.sub.6): 2.27(4H,                                                   brs), 2.73(2H, t), 3.50(4H,                                                   brs), 4.28 (1H, s),                                                           4.35-4.47(2H,                                                                 m), 7.15-8.56(15H, m),                                                        11.88(1H, s)                     __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A                  Melting point (°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1),                   __________________________________________________________________________                                                 NMR(ppm)                         52 Cl                                                                              Ph                                                                              2 1                                                                                ##STR56##         Decomposition point 163                                                                 540  IR(nujol):3400, 3200, 1650                                                    NMR(DMSO-d.sub.6):2.16(4H,                                                    brs), NMR(DMSO-d.sub.6):2.16(                                                 4H, brs), 2.41 (4H, brs),                                                     2.56(2H, t), 4.07(1H, s),                                                     4.67(2H, t), 6.97-7.68(16H,                                                   m)                               53 Cl                                                                              Ph                                                                              2 1                                                                                ##STR57##         161       531  IR(nujol):3200, 1670, 1580                                                    NMR(DMSO-d.sub.6):2.24(4H,                                                    brs), 2.67 (4H, brs),                                                         3.55(2H, t), 3.70 (2H, s),                                                    4.03(2H, t), 4.22(1H, s)                                                      6.89-7.80(14H, m), 11.88(1H,                                                  brs)                             54 Cl                                                                              Ph                                                                              2 1                                                                                ##STR58##         140-141   518  IR(nujol:3350, 1670, 1570                                                     NMR(DMSO-d.sub.6):2.25(4H,                                                    brs), 2.58(4H, brs),                                                          2.84(2H, t), 4.21(1H, s),                                                     4.56(2H, t) 7.17-8.40(14H,                                                    m)                               55 H Py                                                                              2 1                                                                                ##STR59##          -- (powder)                                                                            484  IR(nujol):3250, 3150                                                          NMR(DMSO-d.sub.6):2.16(4H,                                                    brs), 2.78 (2H, t), 3.51(4H,                                                  brs), 4.22(1H, s) 4.31(2H,                                                    t), 6.56(1H, s), 7.07-7.92                                                    (12H, m), 8.39(1H, m),                                                        10.70(1H, brs)                   56 H Ph                                                                              2 1                                                                                ##STR60##         Decomposition point 176                                                                 483  IR(nujol):3190, 1660, 1550                                                    NMR(DMSO-d.sub.6):2.24(4H,                                                    brs), 2.58(4H, brs),                                                          2.83(2H, t) 4.13(1H, s),                                                      4.33(2H, t), 7.12-8.25(16H,                                                   m)                               __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________    Ex. R.sup.1                                                                         B m p A              Melting point (°C.)                                                              MS(M.sup.+)                                                                        IR(C.sup.-1),                       __________________________________________________________________________                                              NMR(ppm)                            57  Cl                                                                              Py                                                                              2 1                                                                                ##STR61##      -- (powder)                                                                            518  IR(nujol):3250,                                                               1640 NMR(DMSO-d.sub.6):2.12(4H,                                               brs), 2.76(2H, t), 3.42(4H,                                                   brs), 4.23(1H, s), 4.30 (2H,                                                  t), 6.55(1H, s), 7.09-7.88(9H,                                                m), 8.40-8.42(1H, m), 10.70(1H,                                               brs)                                58  Cl                                                                              Ph                                                                              2 2                                                                                ##STR62##      -- (powder)                                                                            531  IR(nujol):3350,                                                               1670 NMR(DMSO-d.sub.6):1.66(2H,                                               brs), 2.56(2H, t), 3.00(4H,                                                   brs), 3.10(4H, brs), 4.35(2H,                                                 t), 4.62(1H, s), 6.97-7.72(15H,                                               m)                                  59  H Ph                                                                              2 2                                                                                ##STR63##     99-100    497  NMR(CDCl.sub.3):1.78-1.93(2H,                                                 m), 2.58 (2H, t), 2.64(2H, t),                                                2.97(2H, t), 3.02(2H, t),                                                     3.11(2H, t), 4.35 (2H, t),                                                    4.58(1H, s), 5.96(1H, brs),                                                   6.67-8.08(14H, m), 10.78(1H,                                                  brs)                                __________________________________________________________________________

EXAMPLE 60

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-3,4,5-trimethoxyphenyl-benzamide##STR64##

In 30 ml of ethyl acetate, 676 mg (3.67 mmol) of 3,4,5-trimethoxyanilinewere dissolved. An aqueous solution (20 ml), in which were dissolved 2.0g (3.69 mmol) of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzoic acidchloride.dihydrochloride and 1.24 g of sodium hydrogencarbonate, wasadded to the resulting solution under ice cooling, followed by stirringfor 30 minutes under ice cooling. The ethyl acetate layer was collected,washed successively with 10% sodium hydroxide and water and then, driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. Crude crystals so obtained were recrystallized from amixed solvent of chloroform and isopropyl ether, whereby 1.75 g of thetitle compound were obtained. Yield: 77%.

Melting point (decomposition point): 157°-158° C. MS (m/z): 615(M⁺) IR(nujol) cm⁻¹ : 3320, 1655 NMR (DMSO-d6) δ:

2.16(4H,brs), 2.50(4H,brs), 2.78(2H,t),

3.66(3H,s), 3.73(6H,s), 4.09(1H,s), 4.25(2H,t),

7.03 (2H, s), 7.07-7.78(13H,m), 10.08(1H,s)

EXAMPLES 61-65

Following the procedures of Example 60, the compounds of Examples 61-65shown in Table 13 were obtained. The followings are the names of thecompounds:

EXAMPLE 61

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-(3,5-dimethyl-4-hydroxyphenyl)-benzamide

EXAMPLE 62

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-thiazolidyl-2-yl-benzamide

EXAMPLE 63

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-thiazol-2-yl-benzamide

EXAMPLE 64

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-N-1H-triazol-5-yl-benzamide

EXAMPLE 65

2-[2-[4-(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]benzamide

                                      TABLE 13                                    __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A                  Melting point (°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1),                   __________________________________________________________________________                                                 NMR(ppm)                         61 Cl                                                                              Ph                                                                              2 1                                                                                ##STR65##         Decomposition point 198-200                                                             569  NMR(DMSO-d.sub.6):2.15(10H,                                                   brs), 2.50(4H, brs),                                                          2.77(2H, t), 4.03(1H, s),                                                     4.26(2H, t), 7.05- 7.51(14H,                                                  m), 7.86-7.90(1H, m),                                                         8.13(1H, brs), 9.95(1H, s)       62 Cl                                                                              Ph                                                                              2 1                                                                                ##STR66##          -- (foam)                                                                              535  IR(nujol):3300, 1670             63 Cl                                                                              Ph                                                                              2 1                                                                                ##STR67##         136-138   533  IR(nujol):3250, 1645                                                          NMR(DMSO-d.sub.6):2.24(4H,                                                    brs), 2.51(4H, brs),                                                          2.77(2H, t), 4.18 (1H, s),                                                    4.33(2H, t), 7.07-7.59 (14H,                                                  m), 7.85-7.88(1H, m)             64 Cl                                                                              Ph                                                                              2 1                                                                                ##STR68##          -- (powder)                                                                            517  IR(nujol):3300, 1660                                                          NMR(DMSO-d.sub.6):2.17(4H,                                                    m), 2.50 (4H, m), 2.75(2H,                                                    t), 4.12(1H, s), 4.31(2H,                                                     t), 7.08-7.40(13H, m), 7.52-                                                  .59(1H, m), 7.85-7.89(1H,                                                     m)                               65 Cl                                                                              Ph                                                                              2 1                                                                                ##STR69##         160-161   449  IR(nujol):3400, 1660                                                          NMR(DMSO-d.sub.6):2.31(4H,                                                    brs), 2.49(4H, brs),                                                          2.71(2H, t), 4.20(2H, t),                                                     4.29(1H, s), 6.99- 7.88(13H,                                                  m), 8.20(2H,                     __________________________________________________________________________                                                 brs)                         

EXAMPLE 66

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]amino]benzoicacid ##STR70##

In 1N sodium hydroxide, 800 mg (1.74 mmol) of the1-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazyl]ethoxy]isatin, whichhad been obtained according to the procedures of Example 1, and 3 ml oftetrahydrofuran were dissolved, followed by the dropwise addition of 1ml of a 30% aqueous hydrogen peroxide solution. After having beenstirred at 70° C. for one hour, the reaction mixture was allowed to cooldown and an aqueous solution of sodium sulfite was added. Further,acetic acid was added to the resulting mixture to adjust its pH to 3.Crystals so precipitated were purified by chromatography on a silica gelcolumn (ethyl acetate), whereby 405 mg of the title compound wereobtained. Yield: 52%.

Melting point: 205°-206° C.

MS (m/z): 449(M⁺)

IR (nujol) cm⁻¹ : 3320, 1655 NMR (DMSO-d₆ ) δ: 2.32(4H,brs),2.50(4H,brs), 2.58(2H,t), 3.21(2H,t), 4.27(1H,s), 6.52(1H,t),6.79(1H,d), 7.18(1H,d), 7.26-7.46(11H,m), 7.76(1H,dd)

EXAMPLE 67

Sodium 2-[[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]amino]-α-oxo-phenylacetate ##STR71##

In 5 ml of tetrahydrofuran, 300 mg of1-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazyl]ethoxy]-isatin, whichhad been obtained in accordance with the procedures of Example 1, and0.5 ml of a 1N aqueous sodium hydroxide solution were dissolved,followed by stirring at room temperature for 2 hours. The solvent wasdistilled off under reduced pressure. The residue was thereafterdissolved in water and purifed on polystyrene gel (HP-20), whereby thetitle compound was obtained.

Melting point (decomposition point): 130°-133° C. (sodium salt)

    ______________________________________                                        Elemental analysis:                                                                     C          H      N                                                 ______________________________________                                        Calculated: 64.86        5.44   8.40                                          Found:      64.83        5.70   8.17                                          ______________________________________                                    

EXAMPLE 68

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-(N-1H-tetrazol-5-yl)-benzene##STR72##

In 50 ml of toluene, 4.7 g (10.9 mmol) of the2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]benzonitrile,which had been obtained in Example 13, and 10.9 g (32.7 mmol) oftri-n-butyltin azide were dissolved, followed by refluxing for two days.To the reaction mixture, 5.6 g of benzonitrile were added, followed byfurther refluxing until the excess tri-n-butyltin azide was eliminated.After the reaction mixture was allowed to cool down, the solvent wasdistilled off under reduced pressure. The residue so obtained wasdissolved in a mixed solution of hydrochloric acid, dioxane and ethanol,followed by stirring for one hour. After the solvent was distilled off,a mixed solution of toluene and ethyl ether was added, whereby 4.34 g ofthe title compound were obtained as a precipitate. Yield: 72%.

Melting point: powder (dihydrochloride) MS (m/z): 474(M⁺) IR (nujol)cm⁻¹ : 3400 NMR (DMSO-d6) δ: 2.41(2H,m), 2.65(7H,m), 2.86-2.92(2H,m), 104.19(2H,t), 4.32(2H,t), 6.92-7.54(14H,m), 8.31-8.34 (1H,m)

EXAMPLES 69 & 70

Following the procedures of Example 68, the compounds of Examples 68 and69 shown in Table 14 were obtained. The followings are the names of thecompounds:

EXAMPLE 69

2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-1-tetrazol-5-ylmethyl

EXAMPLE 70

3-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]-[N-1H-tetrazol-5-yl]-benzene

                                      TABLE 14                                    __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A           Melting point (°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                 __________________________________________________________________________    69 Cl                                                                              Ph                                                                              2 1                                                                                ##STR73##  Decomposition point 225 (Dihydrochloride)                                               412  IR(nujol):3450 NMR(DMSO-d.sub.6):(2H                                          Cl)2.60- 3.80(11H, m), 3.95(2H, t),                                           .91(2H, s), 7.38-7.48 (5H, m),                                                7.77(4H, brs)                           70 Cl                                                                              Ph                                                                              2 1                                                                                ##STR74##  220-222 (Dihydrochloride)                                                               474  IR(nujol):3400 NMR(DMSO-d.sub.6):(2H                                          Cl)3.14(4H, brs), 3.20-4.50(9H, m),                                           4.54(2H, brs), 5.33(1H, brs),                                                 7.20-7.75(13H, m)                       __________________________________________________________________________

EXAMPLE 71

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]benzoicacid ##STR75##

In a 15:85 mixed solution of water and tetrahydrofuran, 5.0 g (12 mmol)of2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethylchloride.dihydrochloridewere dissolved, followed by the dropwise addition of 4.0 g (39 mmol) oftriethylamine under an argon stream. To the resulting solution, 2.2 g(14 mmol) of thiosalicylic acid were added and they were stirred at 50°C. for 8 hours. After the reaction mixture was allowed to cool down, thesolvent was distilled off under reduced pressure. Water (200 ml) wasadded to the residue, followed by extraction with 200 ml of ethylacetate. The ethyl acetate layer was dried over anhydrous magnesiumsulfate and the solvent was distilled off. The residue so obtained waspurified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 2.8 g of the title compound were obtained in an oilyform. Yield: 51%.

Melting point: 181-184° C. (hydrochloride) MS (m/z): 466(M⁺) IR (nujol)cm⁻¹ : 2280, 1700, 1590 NMR (DMSO-d6) δ: (dihydrochloride) 3.09(4H,brs),3.35(4H,brs), 3.41(2H,t), 3.60(3H,t), 3.64(1H,s), 7.24-7.93(14H,m)

EXAMPLES 72-74

In accordance with the procedures of Example 71, the compounds ofExamples 72-74 shown in Table 15 were obtained. The followings are thenames of the compounds.

EXAMPLE 72

Ethyl2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]acetate

EXAMPLE 73

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]aceticacid

EXAMPLE 74

2-[[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]nicotinicacid

                                      TABLE 15                                    __________________________________________________________________________    Ex.                                                                              R.sup.1                                                                         B m p A           Melting point (°C.)                                                              MS(M.sup.+)                                                                        IR(cm.sup.-1), NMR(ppm)                 __________________________________________________________________________    72 Cl                                                                              Ph                                                                              2 1 SCH.sub.2 COOCH.sub.2 CH.sub.3                                                             --       432  NMR(DMSO-d.sub.6):(oxalate)1.21(3H,                            (powder)       t), 2.98-3.04(2H, m), 3.26(4H,                                 (Oxalate)      brs), 3.37-3.42(2H, m), 3.50                                                  (2H, s), 3.65(5H, brs), 4.12(2H,                                              q),                                                                           7.35-7.51(4H, m), 7.87(5H, t)           73 Cl                                                                              Ph                                                                              2 1 SCH.sub.2 COOH                                                                            Decomposition                                                                           404  IR(nujol):3450, 1720                                           point 170-172  NMR(DMSO-d.sub.6):(oxalate)2.50                                (Oxalate)      (4H, m), 2.86-2.91(2H, m), 3.20-                                              3.26(6H, m), 3.36(2H, s), 4.50                                                (1H, s), 7.23-7.48(9H, m)               74 Cl                                                                              Ph                                                                              2 1                                                                                ##STR76##   185 (Dihydrochloride)                                                                  467  IR(nujol):3400, 1720,                                                         1560 NMR(DMSO-d.sub.6):(2HCl)2.93                                             (4H, brs), 3.39(4H, brs), 3.60 (2H,                                           t), 4.62(3H, brs), 7.25-8.70(13H,       __________________________________________________________________________                                          m)                                  

EXAMPLE 75

Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]benzoate##STR77##

In 20 ml of anhydrous dichloromethane, 1.1 g (2.36 mmol) of the2-[[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethyl]thio]benzoicacid, which had been obtained in Example 71, were suspended, followed bythe dropwise addition of 0.4 g (3.53 mmol) of thionyl chloride andstirring for 30 minutes, both under ice cooling. After the solvent wasdistilled off under reduced pressure, 20 ml of anhydrous methanol wereadded to the residue and the resulting mixture was stirred at roomtemperature for 30 minutes. The solvent was distilled off under reducedpressure. Water (50 ml) was added to the residue, followed by extractionwith 50 ml of ethyl acetate. The ethyl acetate layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and then driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The residue so obtained was purified by chromatographyon a silica gel column (ethyl acetate:n-hexane =2:1), whereby 0.94 g ofthe title compound was obtained in an oily form. Yield: 85%.

Melting point: 170°-171° C. (hydrochloride) MS (m/z): 480(M⁺) IR (nujol)cm⁻¹ : 2300, 1710, 1590 NMR (DMSO-d₆) δ: (dihydrochloride) 2.38(4H,brs),2.80(4H,brs), 3.17 (2H,t), 3.45(2H,t), 3.83(3H,s), 4.53(1H,s),7.20-7.92(13H,m)

EXAMPLE 76

Methyl [3-[4-(diphenylmethyl)-1-piperazinyl]N-propionyl]anthranilate##STR78##

In 100 ml of toluene, 5.92 g (23.5 mmol) of diphenylmethylpiperazine,5.67 g (23.5 mmol) of methyl N-3-chloropropionylanthranilate and 6.23 g(43.9 mmol) of sodium carbonate were suspended, followed by refluxingfor 12 hours. The reaction mixture was allowed to cool down and waterwas added to it, followed by extraction with ethyl acetate. The ethylacetate layer was washed with water and then dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.The residue so obtained was purified by chromatography on a silica gelcolumn (n-hexane: ethyl acetate =1:2), whereby 9.2 g of the titlecompound were obtained. Yield: 86%.

Melting point: 120°-122° C. MS (m/z): 457(M⁺) IR (nujol) cm⁻¹ : 3280,1710, 1690 NMR (DMSO-d6) δ: 2.31(4H,brs), 2.48(4H,brs), 2.50(2H,t),3.80(3H,s), 4.24(1H,s), 7.13-8.27(14H,m)

    ______________________________________                                        Preparation Example 1                                                         ______________________________________                                        Compound of Example 41                                                                             50 g                                                     Lactose             315 g                                                     Corn starch         125 g                                                     Crystalline cellulose                                                                              25 g                                                     ______________________________________                                    

The above ingredients were mixed uniformly, followed by the addition of200 ml of a 7.5% aqueous solution of hydroxypropylcellulose. Theresultant mixture was granulated through a screen of 0.5 mm in diameterby an extrusion granulator. Immediately after that, the resultantgranules were rounded by a Marumerizer and then dried, whereby granuleswere obtained.

The dried granules so obtained were coated with 1.9 kg of a film coatingsolution of the below-described composition by using a fluidized-bedgranulator, whereby enteric coated granules were obtained.

    ______________________________________                                        Composition of the coating solution:                                          Hydroxypropylmethylcellulose phthalate                                                                 5.0    wt. %                                         Stearic acid             0.25   wt. %                                         Methylene chloride       50.0   wt. %                                         Ethanol                  44.75  wt. %                                         Preparation Example 2                                                         Compound of Example 45   20     g                                             Lactose                  100    g                                             Corn starch              36     g                                             Crystalline cellulose    30     g                                             Carboxymethylcelullose calcium                                                                         10     g                                             Magnesium stearate       4      g                                             ______________________________________                                    

The above ingredients were mixed uniformly and then, pressed into 200-mgtablets by a punch of 7.5 mm in diameter on a single punch tabletingmachine.

A coating solution of the below composition was sprayed to the tabletsto apply 10 mg of a coating per tablet, whereby enteric film-coatedtablets were obtained.

    ______________________________________                                        Composition of the coating solution:                                          Hydroxypropylmethylcellulose phthalate                                                                 8.0    wt. %                                         Glycerin fatty acid ester                                                                              0.4    wt. %                                         Methylene chloride       50.0   wt. %                                         White beeswax            0.1    wt. %                                         Isopropanol              41.5   wt. %                                         Preparation Example 3                                                         Compound of Example 46   100    mg                                            Sodium acetate           2      mg                                            Acetic acid              q.s.                                                 (for adjustment of pH to 5.8)                                                 Distilled water for injection                                                                          q.s.                                                 Total                    10 ml/vial                                           ______________________________________                                    

An injection was obtained according to the above formulation in a mannerknown per se in the art.

    ______________________________________                                        Preparation Example 4                                                         ______________________________________                                        Compound of Example 69 0.1    wt. %                                           Ethanol                20.0   wt. %                                           Liquefied gas ("Propellant 114")                                                                     49.2   wt. %                                           Liquefied gas ("Propellant 12")                                                                      30.7   wt. %                                           ______________________________________                                    

An aerosol was prepared according to the above formulation in a mannerknown per se in the art.

Tests

Test 1 Antihistamic effects

From a Hartley male guinea pig (300-600 g in weight), the ileum wasisolated. The ileum was attached to a holder under a vesting tension of0.5 g in a Magnus bath (30° C., under aeration) filled with 10 ml of theTyrode solution. As a contraction reaction of the isolated ileum causedby histamine (3×10⁻⁷ mole), an isometrical change in muscular tensionwas measured. The ileum was treated with the test compound for 3 minutesbefore the addition of histamine to study its effects and then itsantihistamic action (50% inhibition concentration: IC₅₀ value) wasdetermined.

As a result, each compound showed an IC₅₀ value of from 0.14 to 1.59 μM.Incidentally, the IC₅₀ value of Cetirizine (the compound disclosed inJapanese Patent Laid-Open No. 149282/1982) was determined as a control.Its IC value was 2.40 μM.

Test 2 Antiallergic effects

The back of a male SD rat (150-250 g in weight) was shaved in advance.Physiological saline and 0.1 ml of anti DNP-AS (Dinitrophenyl conjugatedAscaris) IgE serum which had been diluted to a suitable concentrationwith physiological saline were intradermally injected there.Fourty-eight hours after sensitization, the animals were challenged with1 ml of 0.5% Evans blue physiological saline containing 2.5 mg/ml ofDNP-BSA (dinitrophenyl conjugated bovine serum albumin) via the tailvein. Thirty minutes later, they were sacrificed under exsanguinationand the dorsal skin was removed and the exuded dye was measuredaccording to the method proposed by Harada et al. [Allergy, 15,1-7(1966)]. The leaked color amount caused by the passive cutaneousanaphylaxis (PCA) was determined by subtracting the leaked color amountof the site to which physiological saline was administered from that ofthe PCA site. Each test compound was suspended in 5% gum arabic or 0.5%methylcellulose and the-resulting suspension was orally administered atthe rate of 10 mg/4 ml/kg one hour before the administration of antigen.The efficacy of the test compound was evaluated by an ihibition rate(antiallergic effects) of the leaked color amount. The results are shownin Table 16.

                  TABLE 16                                                        ______________________________________                                        Test compound    Antiallergic effects (%)                                     ______________________________________                                        Compound of Example 5                                                                          86.4                                                         (1/2 fumarate)                                                                Compound of Example 9                                                                          61.9                                                         Compound of Example 41                                                                         52.3                                                         (Sodium salt)                                                                 Compound of Example 44                                                                         54.7                                                         Compound of Example 45                                                                         72.4                                                         Compound of Example 46                                                                         59.8                                                         Compound of Example 50                                                                         60.4                                                         Compound of Example 69                                                                         81.0                                                         ______________________________________                                    

Test 3 Toxicity Test

Ten 4-5 week old ICR mice (Charles River Co., Ltd.) were employed ingroups, each consisting of 10 mice. The compounds of the Examples wereseparately suspended in 5% gum arabic. The suspension were each orallyadministered at a dose of 1000 mg/kg and the mice were observed for 7days. As a result, no case of death caused by the toxicity of any of theinvention compounds was observed.

Industrial Applicability

The compounds according to the present invention have strongantihistamic and antiallergic effects and have a high degree of safetyso that they are useful as therapeutic agents for various allergicdiseases, for example, as anti-inflammatory agents, therapeutics fornephritis, hepatitis or pancreatitis, preventives and/or therapeuticsfor respiratory diseases, and anti-asthmatic drugs.

What is claimed is:
 1. A compound of formula (1): ##STR79## or apharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising an effective amount of a compound of formula (1)as claimed in claim 1 or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable auxiliary agent.
 3. A method for treatmentof allergic diseases, which method comprises administering an effectiveamount of a compound of formula (1): ##STR80## or a pharmaceuticallyacceptable salt thereof to a patient suffering from allergic disease. 4.A method as claimed in claim 3 wherein said allergic disease isbronchial asthma.